Schizophrenia-associated LRRTM1 regulates cognitive behavior through controlling synaptic function in the mediodorsal thalamus.

Reduced activity of the mediodorsal thalamus (MD) and abnormal functional connectivity of the MD with the prefrontal cortex (PFC) cause cognitive deficits in schizophrenia. However, the molecular basis of MD hypofunction in schizophrenia is not known. Here, we identified leucine-rich-repeat transmembrane neuronal protein 1 (LRRTM1), a postsynaptic cell-adhesion molecule, as a key regulator of excitatory synaptic function and excitation-inhibition balance in the MD. LRRTM1 is strongly associated with schizophrenia and is highly expressed in the thalamus. Conditional deletion of Lrrtm1 in the MD in adult mice reduced excitatory synaptic function and caused a parallel reduction in the afferent synaptic activity of the PFC, which was reversed by the reintroduction of LRRTM1 in the MD. Our results indicate that chronic reduction of synaptic strength in the MD by targeted deletion of Lrrtm1 functionally disengages the MD from the PFC and may account for cognitive, social, and sensorimotor gating deficits, reminiscent of schizophrenia.

LRRTMs Organize Synapses through Differential Engagement of Neurexin and PTPσ.

Presynaptic neurexins (Nrxs) and type IIa receptor-type protein tyrosine phosphatases (RPTPs) organize synapses through a network of postsynaptic ligands. We show that leucine-rich-repeat transmembrane neuronal proteins (LRRTMs) differentially engage the protein domains of Nrx but require its heparan sulfate (HS) modification to induce presynaptic differentiation. Binding to the HS of Nrx is sufficient for LRRTM3 and LRRTM4 to induce synaptogenesis. We identify mammalian Nrx1γ as a potent synapse organizer and reveal LRRTM4 as its postsynaptic ligand. Mice expressing a mutant form of LRRTM4 that cannot bind to HS show structural and functional deficits at dentate gyrus excitatory synapses. Through the HS of Nrx, LRRTMs also recruit PTPσ to induce presynaptic differentiation but function to varying degrees in its absence. PTPσ forms a robust complex with Nrx, revealing an unexpected interaction between the two presynaptic hubs. These findings underscore the complex interplay of synapse organizers in specifying the molecular logic of a neural circuit.